6. Project Summary/Abstract The development of effective methods for the synthesis of chiral compounds in high enantiomeric purity is of growing economic and biomedical importance. In the pharmaceutical arena, single enantiomer drugs constitute over half of the total drug market. Partly in response to this need, laboratories around the world have directed their efforts to the asymmetric synthesis of chiral compounds. In this renewal proposal, we outline plans for the development and use of novel catalysts for enantioselective synthesis of chiral compounds. Whereas the previous proposal described both metal-based catalysts and hydrogen bonding based catalysts, the current proposal focuses entirely on the latter class of compounds. Unlike traditional metal-based catalysts, the catalysts used in this program are organic molecules that are capable of activating a reactant through the formation of one or more hydrogen bonds. This metal-free acceleration of reactions is not only of fundamental interest, but is also of industrial importance, since metal impurities, especially transition metals, are undesirable in pharmaceutical drugs. The research is divided into two primary areas: catalysis by chiral alcohols and catalysis by chiral squaramides and other novel hydrogen bond donor scaffolds. The range of projects that have been selected for the next funding period represents a balance between feasibility and novelty. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. The research effort will incorporate crystallographic studies and computational methods in order to guide the development of more effective catalysts and to provide an understanding of observed enantioselectivities. Overall, the investigations proposed for the next funding period are expected to lead to the development of broadly useful asymmetric catalysis methodology that will impact many facets of chemical synthesis, including the synthesis of biologically active natural products and pharmaceutical drugs. The projects described herein will provide excellent training for undergraduate students, graduate students, and postdoctoral associates in asymmetric catalysis methodology development, experience that will prepare them well for independent research careers, either in industry or academics.